Lisuride (N-(D-6-methyl-8-isoergolenyl)-N',N'-diethylurea hydrogen maleate) is an ergot derivative. It has alternatively been called ergoline. Lisuride is a serotonin antagonist and has also been reported to be a dopamine agonist. U.S. Pat. No. 3,953,454 describes the preparation of lisuride and its oral administration to animals as an antilactation agent. U.S. Pat. No. 3,681,497 describes its oral administration as a serotonin antagonist to treat migraine headache, urticaria, hypertension, and allergic conditions. U.S. Pat. No. 3,954,988 describes the administration of lisuride orally, by injection, or as an intramuscular depot as a psychic energizer.
U.S. Pat. No. 4,692,452 teaches the treatment of endometritis with lisuride. The patent indicates the drug may be administered orally or by injection. It also postulates that the drug can be administered transdermally through the application of ointments, creams or solutions prepared by combining lisuride with known carriers. No example of transdermal administration is given, and no data relating to the flux of lisuride through the skin are provided. Therefore, at best, this is a speculative teaching that leaves the reader with the task of experimenting to find out whether it is possible to administer lisuride transdermally in vivo at therapeutically effective rates.
Lisuride has also been administered subcutaneously using infusion pumps to reduce on-off motor response fluctuation in Parkinson's patients. J Neural Transm (1988) Suppl 27:85-90. The pharmacokinetics of lisuride following subcutaneous infusion are reported in J Neural Transm (1988) Suppl 27:71-74. For these Parkinson's patients, a constant subcutaneous infusion of 60 micrograms per hour for 12 hours resulted in a mean steady-state plasma level of 0.78.+-.0.19 ng/ml with a range of 0.54 to 1.07 ng/ml.
Numerous patents and publications describe the use of various compounds as skin permeation enhancers. For instance, the use of propylene glycol monolaurate as a permeation enhancer for estradiol and other drugs is described in EPA 874029457.
The present invention is directed to achieving noninvasive sustained administration of lisuride at a controlled rate by delivering it, in combination with a skin permeation enhancer, transdermally from a laminated composite patch affixed to the patient's skin.